Albendazole enantiomeric metabolism and binding to cytosolic proteins in the liver fluke <Emphasis Type="Italic">Fasciola hepatica</Emphasis>

Fascioliasis causes important economic losses in ruminant species all over the world. Its control is largely based on the use of the flukicidal compound triclabendazole (TCBZ). However, its chemically related benzimidazole anthelmintic albendazole (ABZ) is being successfully used to control TCBZ-resistance flukes. This research gains some insights into the comparative molecular behaviour of both anthelmintics within the target fluke. The goals of the current work were: (i) to assess the competitive binding of ABZ and TCBZ to cytosolic proteins of F. hepatica, and (ii) to evaluate the enantioselective biotransformation of ABZ in microsomal fractions obtained from TCBZ-susceptible and TCBZ-resistant strains of the liver fluke. Cytosolic proteins from fluke specimens bound TCBZ with greater affinity (83%) than ABZ (44%) and the fraction of TCBZ bound to cytosolic proteins was not displaced by ABZ. The microsomes from both -susceptible and resistant flukes sulphoxidized ABZ into ABZ sulphoxide (ABZSO). However, this oxidative activity was 49% higher in microsomes from TCBZ-resistant flukes (P < 0.001) with a predominant production of the (+) ABZSO enantiomer. As earlier shown for TCBZ, the results reported here confirm an enhanced ability for ABZ oxidation in TCBZ-resistant flukes. While this enhanced oxidative metabolism of ABZ may cooperate to the resistance phenomenon, other pharmacodynamic-based mechanisms may be involved, which would explain why, although being chemically-related, ABZ remains efficacious against TCBZ resistant flukes under field conditions.     

谱拆分研究O,O-二甲基-1-(4-甲氧基苯氧乙酰氧基)乙基膦酸酯对映体的高效液相色

采用手性固定相高效液相色谱法研究了不同固定相类型、流动相中不同醇改性剂和不同异丙醇含量以及温度对O,O-二甲基-1-(4-甲氧基苯氧乙酰氧基)乙基膦酸酯拆分效果的影响,并初步讨论了它的热力学机理。结果表明:在25℃的直链淀粉-三(-3,5-二甲基氨基甲酸酯)(Chiralpak AD-H)手性柱中,以正已烷∶异丙醇体积90∶10为流动相,流速为1.0 ml/min,检测波长220 nm时,对映体可得到基线分离。     

涂敷型直链淀粉手性固定相的制备及对外消旋体农药喹禾灵的分离研究

不对称分离研究已引起人们广泛的关注 ,高效液相色谱法是其中最重要的研究手段之一 ,它主要包括手性固定相法、流动相添加剂法和衍生化法 ,其中手性固定相法的应用最为广泛。纤维素和淀粉是最易得的具有光学活性的天然聚合物 ,很早就用于手性拆分 [1 ] 。直链淀粉三苯基酯类手性固定相的手性拆分能力较弱 ,但其三苯基氨基甲酸酯类却有很强的手性拆分能力 [2 ]。近年来 ,我们在这一领域进行了探讨 ,并取得了较好结果 [3～ 7]。光学异构体药物往往表现出不同的药代和药理学行为 [8] ,而手性农药也具有相似的特性 ,同一种农药的几种光学异构体…     

Enantiomeric behaviour of albendazole and fenbendazole sulfoxides in domestic animals: Pharmacological implications

Albendazole and fenbendazole are methylcarbamate benzimidazole anthelmintics extensively used to control gastrointestinal parasites in domestic animals. These parent compounds are metabolised to albendazole sulfoxide and fenbendazole sulfoxide (oxfendazole), respectively. Both sulfoxide derivatives are anthelmintically active and are manufactured for use in animals. They metabolites have an asymmetric centre on their chemical structures and two enantiomeric forms of each sulfoxide have been identified in plasma, tissues of parasite location and within target helminths. Both the flavin-monooxygenase and cytochrome P450 systems are involved in the enantioselective biotransformation of these anthelmintic compounds in ruminant species. A relevant progress on the understanding of the relationship among enantioselective metabolism and systemic availability of each enantiomeric form has been achieved. This article reviews the current knowledge on the pharmacological implications of the enantiomeric behaviour of albendazole sulfoxide and oxfendazole in domestic animals.     

微乳液凝胶固定化脂肪酶催化消旋布洛芬辛酯水解反应的研究

初步研究了AOT-正庚烷-明胶微乳液凝胶固定化脂肪酶催化消旋布洛芬辛酯水解反应的影响因素。结果表明:在正庚烷中,布洛芬辛酯水解反应能够顺利进行,产物为光学纯度很高的S-构型布洛芬,转化率为0.3217时,其对映体过量值为0.9826;凝胶R值(水与AOT的摩尔数之比)对酶催化反应有较大影响,最佳R值为73;当酶含量固定,底物浓度为0.10 mol/L时,转化率最大并能得到较高对映体过量值的产物;当反应时间超过16 h时,水解反应达到平衡;固定化酶的重复使用次数与溶剂中的含水量有关,正庚烷中少量的水有助于增加酶的重复使用次数。